Andrew Laccetti: Thank you so much. Happy to be speaking today.
Tanya Dorff: So I'm very interested to hear more about your presentation on the 52-week results from the ARAMON study, which was a study of darolutamide monotherapy in, essentially, a biochemically recurrent population. So the first question that comes to mind is why did we need this study?
Andrew Laccetti: Great question. I'm happy to be reporting on this study that's been developing over the last several years. So as you alluded to, patients with biochemically recurrent prostate cancer, inclusive of those with low-volume metastasis per PSMA PET is a patient population for which we have a great deal of flexibility and opportunity to fine tune our treatment options based upon a focus on quality of life and treatment side effects. So ARAMON was designed as the first formal investigation of darolutamide as monotherapy as a means to treat patients with biochemically recurrent in low-volume metastatic disease in anticipation of a side effect profile that is potentially more favorable.
We chose a biologically relevant endpoint, specifically, testosterone shift, really testing the hypothesis that darolutamide as an AR antagonist that is more so excluded from the central nervous system compared to drugs like enzalutamide or apalutamide may result in a lesser testosterone surge and potentially less gynecomastia and breast tenderness, which is a side effect profile that has plagued AR antagonist monotherapy in the initial Casodex, first-generation AR antagonist landscape, as well as with the more potent agents that we're dealing with. So this is a patient population, again, that's in great need, and we really have an opportunity to improve upon side effect profiles.
Tanya Dorff: So that makes sense. I guess it seems like you chose maybe a slightly less aggressive population than maybe what we would think of in EMBARK where they selected more high-risk features. It seems like almost you were selecting more low risk, and perhaps that's because of that testosterone increase that you were looking for as the primary endpoint?
Andrew Laccetti: Correct. So there's two practical reasons. So the initial design of this trial was actually in the pre-EMBARK era. So establishing an AR monotherapy had not yet moved into a standard of care. You're absolutely right. We were looking to create a smaller single-arm study that would be a proof of principle investigating, really, the biological differences observed between different potent AR antagonists, and we really wanted to leverage a patient population that did not have high-risk features. So specifically, in this trial, we allowed for a PSA doubling time of less than or equal to 20 months, and although we did enroll some patients with bone metastases, this was largely limited to patients that had PSMA PET bone metastases with conventional imaging that was negative.
Tanya Dorff: So I'm sure we'll be interested in some efficacy results too, but to start out with your primary endpoint, what did you guys see with the testosterone levels?
Andrew Laccetti: So yes, so as alluded to, the hypothesis was that as an AR antagonist with a greater degree of central nervous system exclusion, we postulated that darolutamide would result in less negative feedback on the GnRH axis and resultingly less testosterone surge. So we observed at a 12-week study interval, patients had an average of a 53% increase in testosterone, which is significantly less than was observed in trials for enzalutamide and apalutamide monotherapy, for which the testosterone surge was generally over a hundred percent. So our initial hypothesis actually was confirmed in that a lesser degree of testosterone surge was observed, but the next question becomes, is this a clinically meaningful difference? And what was observed was the rates of breast tenderness and gynecomastia were very similar to what was observed in the enza and apa monotherapy trials, ala EMBARK. So although we were achieving a lesser degree of testosterone surge, it was likely above the necessary threshold to produce clinically relevant feminizing side effects.
Tanya Dorff: Interesting. So tell us a little bit about how the prostate cancer responded, I guess PSA results.
Andrew Laccetti: Yeah. So I think outside of the biologic information that was provided by this study, we did demonstrate that darolutamide monotherapy can be an option for select patients who may be non-candidates for AR monotherapy and the other agents. We saw an excellent PSA response with about 65% of patients achieving a PSA decline to less than 0.2 and PSA 90 rates were in the order of around 82%. Even more so, patients' quality of life was extremely well-preserved during the 52-week treatment interval with no significant changes in the FACT-P. We also found that secondary endpoints such as fat metabolism, bone turnover, alterations in other sex hormones were stable throughout the 52-week period. So outside of the feminizing side effects, patients felt exceptionally well, very low fatigue rates, minimal hot flashes, and really no relevant signal for things such as cognitive impairment or personality change. So the efficacy signal was very robust and quality of life was excellent on this treatment option.
Tanya Dorff: So what's next? Are you going to follow these patients and give us a sense of what happens to their disease or what further studies are needed to move this forward?
Andrew Laccetti: Yeah, so I'll give the caveat this was a small phase-two analysis. It was non-randomized and again, the testosterone endpoint was set as the primary endpoint. So these results are exploratory and the efficacy and actually toxicity signals really are hypothesis-generating. As far as plans for this particular study, we have concluded the patient monitoring because importantly, shortly thereafter, discontinuation of darolutamide, testosterone recovers quite quickly. So the effects of the therapy are reversed quite rapidly. We don't have plans to follow for time to next therapy, but I do think that this evidence provides a framework for further investigation of AR monotherapy, potentially in a randomized fashion, because there's a lot more that we can learn of this therapy option compared to other agents, again, such as enza or apa. Then looking more so at more clinically long-term endpoints, time to next therapy, impact on PSA relapse times, and then certainly looking farther into the future, things such as metastasis-free survival. So although this study has concluded its period, I think there's a rich opportunity for further exploration of the study approach.
Tanya Dorff: So it sounds like you think the results were encouraging enough that further exploration of darolutamide monotherapy may be an important step for our patients who are really asking for less metabolic and hot flash symptomatic toxicity.
Andrew Laccetti: I think so. Again, potentially extending this approach outside of the BCR setting, potentially to localized disease. In the clinic, one of the biggest asks for patients, again, in these lower risk scenarios is de-escalation of therapy and strategies by which we can minimize the effects of chemical castration. So I do think darolutamide is chemically unique. It offers the opportunities to avoid drug-drug interactions, and as evidenced by this data, limit blood-brain barrier exposure. So utilizing monotherapy strategies in the biochemically relapsed setting and other scenarios, I think, is an area that strongly warrants further investigation.
Tanya Dorff: Totally agree. Well, thank you so much, Dr. Laccetti, for joining us today to share these results.
Andrew Laccetti: Thank you so much. Pleasure was mine.